Reinforced Vascular Prostheses

ABSTRACT

Vascular grafts for treating, reconstructing and replacing damaged or diseased cardiovascular vessels that are formed from decellularized extracellular matrix (ECM). The vascular grafts include outer or outer and inner coatings that provide structural reinforcement.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.14/337,915, filed on Jul. 22, 2014, which is a continuation-in-part ofU.S. application Ser. No. 14/031,520, filed on Sep. 19, 2013, which is acontinuation-in-part of U.S. application Ser. No. 14/031,423, filed onSep. 19, 2013, which claims the benefit of U.S. Application Nos.61/710,992, filed on Oct. 8, 2012.

FIELD OF THE INVENTION

The present invention relates to methods and apparatus for treatingdamaged or diseased cardiovascular vessels. More particularly, thepresent invention relates to reinforced vascular grafts or prosthesesfor treating and/or reconstructing damaged or diseased cardiovascularvessels.

BACKGROUND OF THE INVENTION

As is well known in the art, various vascular grafts or prostheses areoften employed to treat and reconstruct damaged or diseasedcardiovascular vessels. Currently, the vascular grafts often employed toreconstruct (or replace) damaged or diseased cardiovascular vessels areautologous arteries and veins, e.g., internal mammary artery orsaphenous vein; particularly, in situations where small diameter (i.e.3-4 mm) vessels are required, such as below the knee and coronary arterybypass grafting. Autologous arteries and veins are, however, oftenunavailable, due to prior harvest, or unsuitable, due to arterialdisease.

When autologous arteries and veins are unavailable or unsuitable,synthetic polytatrafluoroethylene (PTFE) or Dacron® grafts are oftenemployed to reconstruct or replace damaged or diseased cardiovascularvessels; particularly, in situations where large diameter (i.e. ≧6 mm)vessels are required.

There are, however, numerous drawbacks and disadvantages associated withsynthetic grafts. A major drawback is the poor median patency exhibitedby synthetic grafts, due to stenosis, thromboembolization, calciumdeposition and infection. Indeed, it has been found that patency is >25%@ 3 years using synthetic and cryopreserved grafts in peripheral andcoronary bypass surgeries, compared to >70% for autologous vasculargrafts. See Chard, et al., Aorta-Coronary Bypass Grafting withPolytetrafluoroethylene Conduits: Early and Late Outcome in EightPatients, j Thorac Cardiovasc Surg, vol. 94, pp. 312-134 (1987).

Decellularized bovine internal jugular xenografts and human allograftvessels from cadavers have also employed to reconstruct or replacedamaged or diseased cardiovascular vessels. Such grafts are, however,prone to calcification and thrombosis and, thus, have not gainedsignificant clinical acceptance.

Vascular prostheses constructed of various biodegradable materials, suchas poly (trimethylene carbonate), have also been developed toreconstruct damaged or diseased cardiovascular vessels. There are,however, several drawbacks and disadvantages associated with suchprostheses.

One major disadvantage is that the biodegradable materials and, hence,prostheses formed therefrom, often break down at a faster rate than isdesirable for the application. A further disadvantage is that thematerials can, and in many instances will, break down into large, rigidfragments that can cause obstructions in the interior of the vessel.

More recently, vascular grafts comprising various remodelable materials,such as extracellular matrix sheets, have been developed to treat andreconstruct damaged or diseased cardiovascular vessels. Illustrative arethe vascular grafts disclosed in Applicant's Co-Pending application Ser.No. 13/573,226.

Although such grafts have garnered overwhelming success and, hence,gained significant clinical acceptance, there are a few drawbacksassociated with such grafts. Among the drawbacks are the constructionand, hence, configuration of the noted vascular grafts.

As discussed in detail in Co-Pending application Ser. No. 13/573,226,such grafts typically comprise one or more sheets of ECM tissue, e.g.,small intestine submucosa, which is secured at one edge to form atubular structure. The secured edge or seam can, and in many instanceswill, disrupt blood flow through the graft. A poorly secured edge alsoposes a significant risk of thrombosis.

Further, in some instances, wherein the ECM graft comprises two or moresheets, i.e. a multi-sheet laminate, such as disclosed in Co-pendingapplication Ser. No. 14/031,423, the laminate structure is prone todelamination.

Thus, readily available, versatile vascular grafts that are not prone tocalcification, thrombosis and intimal hyperplasia would fill asubstantial and growing clinical need.

It is therefore an object of the present invention to provide vasculargrafts (including “endografts”) that substantially reduce or eliminate(i) the risk of thrombosis, (ii) intimal hyperplasia after interventionin a vessel, (iii) the harsh biological responses associated withconventional polymeric and metal prostheses, and (iv) the formation ofbiofilm, inflammation and infection.

It is another object of the present invention to provide vascular graftsthat can effectively replace or improve biological functions or promotethe growth of new tissue in a subject.

It is another object of the present invention to provide vascular graftsthat induce host tissue proliferation, bioremodeling and regeneration ofnew tissue and tissue structures with site-specific structural andfunctional properties.

It is another object of the present invention to provide vascular graftsthat are capable of administering a pharmacological agent to host tissueand, thereby produce a desired biological and/or therapeutic effect.

SUMMARY OF THE INVENTION

The present invention is directed to vascular grafts or prostheses fortreating, reconstructing or replacing damaged or diseased cardiovascularvessels.

As discussed in detail herein, in a preferred embodiment, the vasculargrafts comprise coated tubular members having proximal and distal ends.

In some embodiments of the invention, the tubular members comprise adecellularized ECM material derived from a mammalian tissue source, i.e.tubular ECM members.

According to the invention, the ECM material can be derived from variousmammalian tissue sources, including, without limitation, small intestinesubmucosa (SIS), urinary bladder submucosa (UBS), stomach submucosa(SS), mesothelial tissue, placental extracellular matrix, omomentumextracellular matrix, and cardiac extracellular matrix.

In a preferred embodiment, the mammalian tissue source comprises anadolescent mammalian tissue source.

In some embodiments, the tubular members comprise an ECM/ECM-mimickingbiomaterial composition comprising an ECM material and an ECM-mimickingbiomaterial, such as poly(glycerol sebacate) (PGS).

In some embodiments of the invention, the tubular member coatingcomprises a polymeric composition comprising a biodegradable polymericmaterial, such as poly(ε-caprolactone) (PCL).

In some embodiments of the invention, the tubular member coatingcomprises an ECM composition comprising at least one ECM material.

In some embodiments of the invention, the tubular member coatingcomprises an ECM-mimicking biomaterial composition comprising at leastone ECM-mimicking biomaterial.

In some embodiments of the invention, the tubular members furthercomprise an outer reinforcing structure.

In some embodiments of the invention, the reinforcing structurecomprises a thin member, such as a strand, that is wound about the outersurface of the tubular member.

In some embodiments of the invention, the reinforcing structurecomprises a mesh or woven structure.

In some embodiments of the invention, the reinforcing structurecomprises an ECM-mimicking biomaterial, such as PGS.

In some embodiments of the invention, the tubular members and, hence,vascular grafts formed therefrom, further comprise at least oneadditional biologically active agent or composition, i.e. an agent thatinduces or modulates a physiological or biological process, or cellularactivity, e.g., induces proliferation, and/or growth and/or regenerationof tissue.

In some embodiments, the biologically active agent comprises a cell,such as, without limitation, a human embryonic stern cell, fetalcardiomyocyte, myofibroblast, and mesenchymal stem cell.

In some embodiments, the biologically active agent comprises a growthfactor, such as, without limitation, a transforming growth factor-alpha(TGF-α), transforming growth factor-beta (TGF-β), fibroblast growthfactor-2 (FGF-2), basic fibroblast growth factor (bFGF), and vascularepithelial growth factor (VEGF).

In some embodiments, the tubular members and, hence, vascular graftsformed therefrom, further comprise at least one pharmacological agent orcomposition (or drug), i.e. an agent or composition that is capable ofproducing a desired biological effect in vivo, e.g., stimulation orsuppression of apoptosis, stimulation or suppression of an immuneresponse, etc.

Suitable pharmacological agents and compositions include, withoutlimitation, antibiotics, anti-viral agents, analgesics,anti-inflammatories, anti-neoplastics, anti-spasmodics, andanticoagulants and/or antithrombic agents.

In some embodiments of the invention, the pharmacological agentcomprises a statin, i.e. a HMG-CoA reductase inhibitor, such ascerivastatin.

In some embodiments of the invention, the vascular graft and/or coatingprovides a single-stage agent delivery profile, i.e. comprise asingle-stage agent delivery vehicle, wherein a modulated dosage of anaforementioned biologically active and/or pharmacological agent isprovided.

In some embodiments of the invention, the vascular graft and/or coatingprovides a multi-stage agent delivery profile, i.e. comprise amulti-stage delivery vehicle, wherein a plurality of the aforementionedbiologically active and/or pharmacological agents are administered via amodulated dosage.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages will become apparent from the followingand more particular description of the preferred embodiments of theinvention, as illustrated in the accompanying drawings, and in whichlike referenced characters generally refer to the same parts or elementsthroughout the views, and in which:

FIG. 1A is a perspective view of one embodiment of a tubular ECM member,in accordance with the invention;

FIG. 1B is a side or edge plan view of the tubular ECM member shown inFIG. 1A, in accordance with the invention;

FIG. 2A is a perspective view of one embodiment of a coated ECM vasculargraft, in accordance with the invention;

FIG. 2B is a side or edge plan view of the coated ECM vascular graftshown in FIG. 2A, in accordance with the invention;

FIG. 3A is a perspective view of another embodiment of a coated ECMvascular graft, in accordance with the invention; and

FIG. 3B is a side or edge plan view of the coated ECM vascular graftshown in FIG. 3A, in accordance with the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particularlyexemplified apparatus, systems, structures or methods as such may, ofcourse, vary. Thus, although a number of apparatus, systems and methodssimilar or equivalent to those described herein can be used in thepractice of the present invention, the preferred apparatus, systems,structures and methods are described herein.

It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments of the invention only andis not intended to be limiting.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one having ordinaryskill in the art to which the invention pertains.

Further, all publications, patents and patent applications cited herein,whether supra or infra, are hereby incorporated by reference in theirentirety.

As used in this specification and the appended claims, the singularforms “a, “an” and “the” include plural referents unless the contentclearly dictates otherwise. Thus, for example, reference to “apharmacological agent” includes two or more such agents and the like.

Further, ranges can be expressed herein as from “about” or“approximately” one particular value, and/or to “about” or“approximately” another particular value. When such a range isexpressed, another embodiment includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by use of the antecedent “about” or“approximately”, it will be understood that the particular value formsanother embodiment. It will be further understood that the endpoints ofeach of the ranges are significant both in relation to the otherendpoint, and independently of the other endpoint.

It is also understood that there are a number of values disclosedherein, and that each value is also herein disclosed as “about” or“approximately” that particular value in addition to the value itself.For example, if the value “10” is disclosed, then “approximately 10” isalso disclosed. It is also understood that when a value is disclosedthat “less than or equal to” the value, “greater than or equal to thevalue” and possible ranges between values are also disclosed, asappropriately understood by the skilled artisan. For example, if thevalue “10” is disclosed then “less than or equal to 10” as well as“greater than or equal to 10” is also disclosed.

DEFINITIONS

The terms “graft” and “endograft” are used interchangeably herein, andmean and include a structure that is configured for implantation in acardiovascular structure, e.g., a cardiovascular vessel.

The terms “extracellular matrix” and “ECM” are used interchangeablyherein, and mean and include a collagen-rich substance that is found inbetween cells in mammalian tissue, and any material processed therefrom,e.g. decellularized ECM. According to the invention, the ECM materialcan be derived from various mammalian tissue sources including, withoutlimitation, the small intestine, large intestine, stomach, lung, liver,kidney, pancreas, placenta, heart, bladder, prostate, tissue surroundinggrowing enamel, tissue surrounding growing bone, and any fetal tissuefrom any mammalian organ.

The ECM material can thus comprise, without limitation, small intestinesubmucosa (SIS), urinary bladder submucosa (UBS), stomach submucosa(SS), central nervous system tissue, dermal extracellular matrix,subcutaneous extracellular matrix, gastrointestinal extracellularmatrix, i.e. large and small intestines, tissue surrounding growingbone, placental extracellular matrix, ornomentum extracellular matrix,epithelium of mesodermal origin, i.e. mesothelial tissue, cardiacextracellular matrix, e.g., pericardium and/or myocardium, kidneyextracellular matrix, pancreas extracellular matrix, lung extracellularmatrix, and combinations thereof. The ECM material can also comprisecollagen from mammalian sources.

The terms “urinary bladder submucosa (UBS)”, “small intestine submucosa(SIS)” and “stomach submucosa (SS)” also mean and include any UBS and/orSIS and/or SS material that includes the tunica mucosa (which includesthe transitional epithelial layer and the tunica propria), submucosallayer, one or more layers of muscularis, and adventitia (a looseconnective tissue layer) associated therewith.

The ECM material can also be derived from basement membrane of mammaliantissue/organs, including, without limitation, urinary basement membrane(UBM), liver basement membrane (LBM), and amnion, chorion, allograftpericardium, allograft acellular dermis, amniotic membrane, Wharton'sjelly, and combinations thereof.

Additional sources of mammalian basement membrane include, withoutlimitation, spleen, lymph nodes, salivary glands, prostate, pancreas andother secreting glands.

The ECM material can also be derived from other sources, including,without limitation, collagen from plant sources and synthesizedextracellular matrices, i.e. cell cultures.

The term “angiogenesis”, as used herein, means a physiologic processinvolving the growth of new blood vessels from pre-existing bloodvessels.

The term “neovascularization”, as used herein, means and includes theformation of functional vascular networks that can be perfused by bloodor blood components. Neovascularization includes angiogenesis, buddingangiogenesis, intussuceptive angiogenesis, sprouting angiogenesis,therapeutic angiogenesis and vasculogenesis.

The term “Artelon™”, as used herein, means a poly(urethane urea)material distributed by Artimplant AB in Goteborg, Sweden.

The terms “ECM-mimicking material” and “ECM-mimicking biomaterial” areused interchangeably herein, and mean and include a biodegradablematerial that induces neovascularization and bioremodeling of tissue invivo, i.e. when disposed proximate damaged biological tissue. The terms“ECM-mimicking material” and “ECM-mimicking biomaterial” thus include,without limitation, ECM-mimicking polymeric biomaterials; specifically,poly(glycerol sebacate) (PGS).

The terms “biologically active agent” and “biologically activecomposition” are used interchangeably herein, and mean and include agentthat induces or modulates a physiological or biological process, orcellular activity, e.g., induces proliferation, and/or growth and/orregeneration of tissue.

The terms “biologically active agent” and “biologically activecomposition” thus mean and include, without limitation, the followinggrowth factors: platelet derived growth factor (PDGF), epidermal growthfactor (EGF), transforming growth factor alpha (TGF-alpha), transforminggrowth factor beta (TGF-beta), fibroblast growth factor-2 (FGF-2), basicfibroblast growth factor (bFGF), vascular epithelial growth factor(VEGF), hepatocyte growth factor (HGF), insulin-like growth factor(IGF), nerve growth factor (NGF), platlet derived growth factor (PDGF),tumor necrosis factor alpha (TNA-alpha), and placental growth factor(PLGF).

The terms “biologically active agent” and “biologically activecomposition” also mean and include, without limitation, human embryonicstem cells, fetal cardiomyocytes, myofibroblasts, mesenchymal stemcells, autotransplated expanded cardiomyocytes, adipocytes, totipotentcells, pluripotent cells, blood stem cells, myoblasts, adult stem cells,bone marrow cells, mesenchymal cells, embryonic stem cells, parenchymalcells, epithelial cells, endothelial cells, mesothelial cells,fibroblasts, osteoblasts, chondrocytes, exogenous cells, endogenouscells, stern cells, hematopoietic stem cells, bone-marrow derivedprogenitor cells, myocardial cells, skeletal cells, fetal cells,undifferentiated cells, multi-potent progenitor cells, unipotentprogenitor cells, monocytes, cardiac myoblasts, skeletal myoblasts,macrophages, capillary endothelial cells, xenogenic cells, allogeniccells, and post-natal stem cells.

The terms “biologically active agent” and “biologically activecomposition” also mean and include, without limitation, the followingbiologically active agents (referred to interchangeably herein as a“protein”, “peptide” and “polypeptide”): collagen (types I-V),proteoglycans, glycosaminoglycans (GAGs), glycoproteins, growth factors,cytokines, cell-surface associated proteins, cell adhesion molecules(CAM), angiogenic growth factors, endothelial ligands, matrikines,cadherins, immuoglobins, fibril collagens, non-fibrallar collagens,basement membrane collagens, multiplexins, small-leucine richproteoglycans, decorins, biglycans, fibromodulins, keratocans, lumicans,epiphycans, heparin sulfate proteoglycans, perlecans, agrins, testicans,syndecans, glypicans, serglycins, selectins, lecticans, aggrecans,versicans, neurocans, brevicans, cytoplasmic domain-44 (CD-44),macrophage stimulating factors, amyloid precursor proteins, heparins,chondroitin sulfate B (dermatan sulfate), chondroitin sulfate A, heparinsulfates, hyaluronic acids, fibronectins, tenascins, elastins,fibrillins, laminins, nidogen/enactins, fibulin I, fibulin II,integrins, transmembrane molecules, thrombospondins, ostepontins, andangiotensin converting enzymes (ACE).

The terms “pharmacological agent”, “active agent”, “drug” and “activeagent formulation” are used interchangeably herein, and mean and includean agent, drug, compound, composition of matter or mixture thereof,including its formulation, which provides some therapeutic, oftenbeneficial, effect. This includes any physiologically orpharmacologically active substance that produces a localized or systemiceffect or effects in animals, including warm blooded mammals, humans andprimates; avians; domestic household or farm animals, such as cats,dogs, sheep, goats, cattle, horses and pigs; laboratory animals, such asmice, rats and guinea pigs; fish; reptiles; zoo and wild animals; andthe like.

The terms “pharmacological agent”, “active agent”, “drug” and “activeagent formulation” thus mean and include, without limitation,antibiotics, anti-arrhythmic agents, anti-viral agents, analgesics,steroidal anti-inflammatories, non-steroidal anti-inflammatories,anti-neoplastics, anti-spasmodics, modulators of cell-extracellularmatrix interactions, proteins, hormones, growth factors, matrixmetalloproteinases (MMPS), enzymes and enzyme inhibitors, anticoagulantsand/or antithrombic agents, DNA, RNA, modified DNA and RNA, NSAIDs,inhibitors of DNA, RNA or protein synthesis, polypeptides,oligonucleotides, polynucleotides, nucleoproteins, compounds modulatingcell migration, compounds modulating proliferation and growth of tissue,and vasodilating agents.

The terms “pharmacological agent”, “active agent”, “drug” and “activeagent formulation” thus include, without limitation, atropine,tropicamide, dexamethasone, dexamethasone phosphate, betamethasone,betamethasone phosphate, prednisolone, triamcinolone, triamcinoloneacetonide, fluocinolone acetonide, anecortave acetate, budesonide,cyclosporine, FK-506, rapamycin, ruboxistaurin, midostaurin,flurbiprofen, suprofen, ketoprofen, diclofenac, ketorolac, nepafenac,lidocaine, neomycin, polymyxin b, bacitracin, gramicidin, gentamicin,oyxtetracycline, ciprofloxacin, ofloxacin, tobramycin, amikacin,vancomycin, cefazolin, ticarcillin, chloramphenicol, miconazole,itraconazole, trifluridine, vidarabine, ganciclovir, acyclovir,cidofovir, ara-amp, foscarnet, idoxuridine, adefovir dipivoxil,methotrexate, carboplatin, phenylephrine, epinephrine, dipivefrin,timolol, 6-hydroxydopamine, betaxolol, pilocarpine, carbachol,physostigmine, demecarium, dorzolamide, brinzolamide, latanoprost,sodium hyaluronate, insulin, verteporfin, pegaptanib, ranibizumab, andother antibodies, antineoplastics, anti-VEGFs, ciliary neurotrophicfactor, brain-derived neurotrophic factor, bFGF, Caspase-1 inhibitors,Caspase-3 inhibitors, α-Adrenoceptors agonists, NMDA antagonists, Glialcell line-derived neurotrophic factors (GDNF), pigmentepithelium-derived factor (PEDF), and NT-3, NT-4, NGF, IGF-2. The terms“pharmacological agent”, “active agent”, “drug” and “active agentformulation” further mean and include the following Class I-Class Vantiarrhythmic agents: (Class Ia) quinidine, procainamide anddisopyramide; (Class Ib) lidocaine, phenyloin and mexiletine; (Class Ic)flecamide, propafenone and moricizine; (Class II) propranolol, esmolol,timolol, metoprolol and atenolol; (Class III) amiodarone, sotalol,ibutilide and dofetilide; (Class IV) verapamil and diltiazem) and (ClassV) adenosine and digoxin.

The terms “pharmacological agent”, “active agent”, “drug” and “activeagent formulation” further mean and include, without limitation, thefollowing antiobiotics: aminoglycosides, cephalosporins,chloramphenicol, clindamycin, erythromycins, fluoroquinolones,macrolides, azolides, metronidazole, penicillins, tetracyclines,trimethoprim-sulfamethoxazole and vancomycin.

The terms “pharmacological agent”, “active agent”, “drug” and “activeagent formulation” further include, without limitation, the followingsteroids: andranes (e.g., testosterone), cholestanes, cholic acids,corticosteroids (e.g., dexamethasone), estraenes (e.g., estradiol) andpregnanes (e.g., progesterone).

The terms “pharmacological agent”, “active agent”, “drug” and “activeagent formulation” can further include one or more classes of narcoticanalgesics, including, without limitation, morphine, codeine, heroin,hydromorphone, levorphanol, meperidine, methadone, oxycodone,propoxyphene, fentanyl, methadone, naloxone, buprenorphine, butorphanol,nalbuphine and pentazocine.

The terms “pharmacological agent”, “active agent”, “drug” and “activeagent formulation” can further include one or more classes of topical orlocal anesthetics, including, without limitation, esters, such asbenzocaine, chloroprocaine, cocaine, cyclomethycaine,dimethocaine/larocaine, piperocaine, propoxycaine, procaine/novacaine,proparacaine, and tetracaine/amethocaine. Local anesthetics can alsoinclude, without limitation, amides, such as articaine, bupivacaine,cinchocaine/dibucaine, etidocaine, levobupivacaine,lidocaine/lignocaine, mepivacaine, prilocalne, ropivacaine, andtrimecaine. Local anesthetics can further include combinations of theabove from either amides or esters.

The terms “anti-inflammatory” and “anti-inflammatory agent” are alsoused interchangeably herein, and mean and include a “pharmacologicalagent” and/or “active agent formulation”, which, when a therapeuticallyeffective amount is administered to a subject, prevents or treats bodilytissue inflammation i.e. the protective tissue response to injury ordestruction of tissues, which serves to destroy, dilute, or wall offboth the injurious agent and the injured tissues.

Anti-inflammatory agents thus include, without limitation, alclofenac,alclometasone dipropionate, algestone acetonide, alpha amylase,amcinafal, amcinafide, amfenac sodium, amiprilose hydrochloride,anakinra, anirolac, anitrazafen, apazone, balsalazide disodium,bendazac, benoxaprofen, benzydamine hydrochloride, bromelains,broperamole, budesonide, carprofen, cicloprofen, cintazone, carprofen,clobetasol propionate, clobetasone butyrate, clopirac, cloticasonepropionate, cormethasone acetate, cortodoxone, decanoate, deflazacort,delatestryl, depo-testosterone, desonide, desoximetasone, dexamethasonedipropionate, diclofenac potassium, diclofenac sodium, diflorasonediacetate, diflumidone sodium, diflunisal, difluprednate, diftalone,dimethyl sulfoxide, drocinonide, endrysone, enlimomab, enolicam sodium,epirizole, etodolac, etofenamate, felbinac, fenamole, fenbufen,fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac, flazalone,fluazacort, flufenamic acid, flumizole, flunisolide acetate, flunixin,flunixin meglumine, fluocortin butyl, fluorometholone acetate,fluquazone, flurbiprofen, fluretofen, fluticasone propionate,furaprofen, furobufen, halcinonide, halobetasol propionate, halopredoneacetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol,ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxole,intrazole, isoflupredone acetate, isoxepac, isoxicam, ketoprofen,lofemizole hydrochloride, lomoxicam, loteprednol etabonate,meclofenamate sodium, meclofenamic acid, meclorisone dibutyrate,mefenamic acid, mesalamine, meseclazone, mesterolone,methandrostenolone, methenolone, methenolone acetate, methylprednisolonesuleptanate, morniflumate, nabumetone, nandrolone, naproxen, naproxensodium, naproxol, nimazone, olsalazine sodium, orgotein, orpanoxin,oxandrolane, oxaprozin, oxyphenbutazone, oxymetholone, paranylinehydrochloride, pentosan polysulfate sodium, phenbutazone sodiumglycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicamolamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone,proxazole, proxazole citrate, rimexolone, romazarit, salcolex,salnacedin, salsalate, sanguinarium chloride, seclazone, sermetacin,stanozolol, sudoxicam, sulindac, suprofen, talmetacin, talniflumate,talosalate, tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam,tesimide, testosterone, testosterone blends, tetrydamine, tiopinac,tixocortol pivalate, tolmetin, tolmetin sodium, triclonide,triflumidate, zidometacin, and zomepirac sodium.

The term “pharmacological composition”, as used herein, means andincludes a composition comprising a “pharmacological agent” and/or a“biologically active agent” and/or any additional agent or componentidentified herein.

The term “therapeutically effective”, as used herein, means that theamount of the “pharmacological agent” and/or “biologically active agent”and/or “pharmacological composition” administered is of sufficientquantity to ameliorate one or more causes, symptoms, or sequelae of adisease or disorder. Such amelioration only requires a reduction oralteration, not necessarily elimination, of the cause, symptom, orsequelae of a disease or disorder.

The term “adolescent”, as used herein, means and includes a mammal thatis preferably less than three (3) years of age.

The terms “patient” and “subject” are used interchangeably herein, andmean and include warm blooded mammals, humans and primates; avians;domestic household or farm animals, such as cats, dogs, sheep, goats,cattle, horses and pigs; laboratory animals, such as mice, rats andguinea pigs; fish; reptiles; zoo and wild animals; and the like.

The term “comprise” and variations of the term, such as “comprising” and“comprises,” means “including, but not limited to” and is not intendedto exclude, for example, other additives, components, integers or steps.

The following disclosure is provided to further explain in an enablingfashion the best modes of performing one or more embodiments of thepresent invention. The disclosure is further offered to enhance anunderstanding and appreciation for the inventive principles andadvantages thereof, rather than to limit in any manner the invention.The invention is defined solely by the appended claims including anyamendments made during the pendency of this application and allequivalents of those claims as issued.

As stated above, the present invention is directed to vascular grafts orprostheses for treating, reconstructing or replacing damaged or diseasedtissue.

It is, however, understood that, although the disclosure is directed tovascular grafts, the invention is also applicable to coated planarmembers.

In a preferred embodiment, the vascular grafts comprise coated tubularmembers having proximal and distal ends.

In some embodiments of the invention, the tubular members comprise anECM material derived from a mammalian tissue source. According to theinvention, the mammalian tissue sources can include, without limitation,the small intestine, large intestine, stomach, lung, liver, kidney,pancreas, placenta, heart, bladder, prostate, tissue surrounding growingenamel, tissue surrounding growing bone, and any fetal tissue from anymammalian organ.

As discussed in detail herein, in a preferred embodiment, the ECMmaterial comprises ECM selected from the group comprising, withoutlimitation, SIS, UBS, SS, central nervous system tissue, dermalextracellular matrix, subcutaneous extracellular matrix,gastrointestinal extracellular matrix, tissue surrounding growing bone,placental extracellular matrix, ornomentum extracellular matrix,mesothelial tissue, cardiac extracellular matrix, kidney extracellularmatrix, pancreas extracellular matrix, lung extracellular matrix, andcombinations thereof.

Preferably, the mammalian tissue source comprises an adolescentmammalian tissue source, i.e. an adolescent mammal, such as a piglet,which is preferably less than three (3) years of age.

In a preferred embodiment, the ECM material is decellularized and,hence, remodelable.

According to the invention, the ECM material can be decellularized byvarious conventional means. In a preferred embodiment, the ECM materialis decellularized via one of the unique Novasterilis processes disclosedin U.S. Pat. No. 7,108,832 and U.S. patent application Ser. No.13/480,204; which are incorporated by reference herein in theirentirety.

In some embodiments of the invention, the tubular members comprise anECM/ECM-mimicking biomaterial composition comprising an ECM material andan ECM-mimicking biomaterial.

In a preferred embodiment, the ECM-mimicking biomaterial comprisespoly(glycerol sebacate) (PGS).

As discussed in detail below, Applicant has found that PGS exhibitsnumerous beneficial properties that provide several beneficialbiochemical actions or activities.

PGS Physical Properties

PGS is a condensate of the non-immunogenic compositions glycerol (asimple sugar alcohol) and sebacic acid (a naturally occurringdicarboxylic acid), wherein, glycerol and sebacic acid are readilymetabolized when proximate mammalian tissue. The non-immunogenicproperties substantially limit the acute inflammatory responsestypically associated with other “biocompatible” polymers, such as ePTFE(polytetrafluoroethylene), that are detrimental to bioremodeling andtissue regeneration.

The mechanical properties of PGS are substantially similar to that ofbiological tissue. Indeed, the value of the Young's modulus of PGS isbetween that of a ligament (in KPa range) and tendon (in GPa range). Thestrain to failure of PGS is also similar to that of arteries and veins(i.e. over 260% elongation).

The tensile strength of the PGS is at least 0.28±0.004 MPa. The Young'smodulus and elongation are at least 0.122±0.0003 and at least237.8±0.64%, respectively. For applications requiring strongermechanical properties and a slower biodegradation rate, PGS can beblended with PCL, i.e. a biodegradable elastomer.

ECM Mimicking Properties/Actions

It has been established that PGS induces tissue remodeling andregeneration when administered proximate to damaged tissue, thus,mimicking the seminal regenerative properties of ECM and, hence, an ECMcomposition formed therefrom. The mechanism underlying this behavior isdeemed to be based on the mechanical and biodegradation kinetics of thePGS. See Sant, et al., Effect of Biodegradation and de novo MatrixSynthesis on the Mechanical Properties of VIC-seeded PGS-PCL scaffolds,Acta. Biomater., vol. 9(4), pp. 5963-73 (2013).

In some embodiments, the ECM/ECM-mimicking biomaterial compositionfurther comprises PCL, which, according to the invention, modulates thedegradation characteristics of the composition and, hence, tubularmember formed therewith.

In some embodiments, the ECM/ECM-mimicking biomaterial tubular membersare formed via a Novasterilis process disclosed in U.S. Pat. No.7,108,832 and U.S. patent application Ser. No. 13/480,204, wherein thePGS (and PCL, if employed) is driven into an ECM tubular member.

In some embodiments, the tubular members comprise a mesh structure, suchas disclosed in U.S. patent application Ser. Nos. 14/554,730, 14/554,795and 14/554,847, filed on Nov. 26, 2014.

In some embodiments, the mesh structure is embedded in the tubularmember.

In some embodiments, the mesh structure is disposed over the luminalsurface of the tubular member.

In some embodiments of the invention, the tubular member coatingcomprises a polymeric composition comprising at least one biocompatiblepolymeric material.

According to the invention, the biocompatible polymeric material cancomprise, without limitation, polyglycolide (PGA), polylactide (PLA),poly(s-caprolactone) (PCL), poly dioxanone (a polyether-ester), polylactide-co-glycolide, polyamide esters, polyalkalene esters, polyvinylesters, polyvinyl alcohol, and polyanhydrides, and like polymers.

The biocompatible polymeric material can also comprise, withoutlimitation, natural polymeric materials, including, without limitation,polysaccharides (e.g. starch and cellulose), proteins (e.g., gelatin,casein, silk, wool, etc.), and polyesters (e.g., polyhydroxyalkanoates).

In some embodiments of the invention, the coating comprises a polymericcomposition comprising a biocompatible polymeric material selected fromthe group comprising, without limitation, polyhydroxyalkonates (PHAs),polylactides (PLLA) and polyglycolides (PLGA) and their copolymers, forexample poly(ε-caprolactone-co-glycolide), polyanhydrides, and likepolymers.

According to the invention, the polymeric material can also comprise ahydrogel, including, without limitation, polyurethane, poly(ethyleneglycol), polypropylene glycol), poly(vinylpyrrolidone), xanthan, methylcellulose, carboxymethyl cellulose, alginate, hyaluronan, poly(acrylicacid), polyvinyl alcohol, acrylic acid, hydroxypropyl methyl cellulose,methacrylic acid, αβ-glycerophosphate, κ-carrageenan,2-acrylamido-2-methylpropanesulfonic acid, and β-hairpin peptide.

In some embodiments, the hydrogel is crosslinked via chemically and/orphotocuring, e.g. ultraviolet light.

In some embodiments, the polymeric material is plasma treated toaccommodate hygroscopic agents.

In some embodiments of the invention, the tubular member coatingcomprises an ECM composition comprising at least one of theaforementioned ECM materials.

Suitable ECM compositions are disclosed in U.S. Pat. Nos. 8,568,761,8,753,885, 8,795,728, 8,734,841, 8,642,084, 8,771,737, 8,734,842,8,784,891, 8,753,886, 8,785,197, 8,785,198, 8,735,155 and U.S. patentapplication Ser. No. 13/732,943, filed on Jan. 2, 2013, Ser. No.11/448,351, filed on Jun. 6, 2006, Ser. No. 14/269,324, filed on May 5,2014, Ser. No. 13/732,558, filed on Jan. 2, 2013, Ser. No. 13/732,731,filed on Jan. 2, 2013, Ser. No. 13/875,017, filed on May 1, 2013, Ser.No. 13/875,043, filed on May 1, 2013, Ser. No. 13/875,058, filed on May1, 2013, Ser. No. 14/452,707, filed on Aug. 6, 2014, Ser. No.14/192,973, filed on Jan. 28, 2014, Ser. No. 14/192,992, filed on Feb.28, 2014, Ser. No. 14/193,008, filed on Feb. 28, 2014, Ser. No.14/193,030, filed on Feb. 28, 2014, Ser. No. 14/193,053, filed on Feb.28, 2014, Ser. No. 14/269,414, filed on Mar. 3, 2013, Ser. No.14/269,487, filed on Mar. 3, 2013, Ser. No. 14/269,874, filed on Mar. 3,2013, Ser. No. 14/337,460, filed on Mar. 3, 2013; which are incorporatedby reference herein in their entirety.

In some embodiments of the invention, the tubular member coatingcomprises an ECM-mimicking composition comprising at least oneECM-mimicking biomaterial.

In a preferred embodiment, the ECM-mimicking biomaterial comprises PGS.

In some embodiments of the invention, the tubular member coatingcomprises an ECM-mimicking composition comprising PGS and PCL.

In some embodiments of the invention, the tubular member coatingcomprises an ECM/ECM-mimicking biomaterial composition, e.g. 50% ECM/50%PGS.

In some embodiments, the ECM/ECM-mimicking biomaterial compositionfurther comprises PCL.

In some embodiments, the tubular member coating comprises a blendedplurality of ECM, polymeric, ECM-mimicking biomaterial composition,and/or ECM/ECM-mimicking biomaterial composition coatings.

In some embodiments, the tubular member coating comprises a porosity inthe range of 10-90%.

In some embodiments, the tubular member coating comprises a thickness inthe range of 5-100 μm, which can vary based on the orientation and thesize of the vascular grafts. In some embodiments, the coating thicknessis in the range of 10-20 μm. If multiple coatings are employed, thetotal coating thickness is preferably in the range of 5-200 μm, morepreferably, in the range of 30-80 μm.

According to the invention, the tubular member coating(s) can be appliedto the tubular member by various conventional means, including, withoutlimitation, pressure coating in a vapor chamber, dip coating, andspraying.

In some embodiments of the invention, the tubular members furthercomprise an outer reinforcing structure, such as disclosed in Co-pendingU.S. application Ser. No. 14/337,863, filed on Jul. 22, 2014, and Ser.Nos. 14/554,730, 14/554,795 and 14/554,847, filed on Nov. 26, 2014,which are incorporated by reference herein in their entirety.

According to the invention, the reinforcing structure can comprise awound member or strand configuration, i.e. a thin strand wound aroundthe outer surface of the tubular member, such as disclosed in Co-Pendingapplication Ser. No. 14/337,863 or a mesh structure, such as disclosedin Co-Pending application Ser. Nos. 14/554,730, 14/554,795 and14/554,847.

In some embodiments of the invention, the reinforcing structurecomprises one of the aforementioned ECM materials.

In some embodiments, the reinforcing structure comprises one of theaforementioned polymeric materials.

In some embodiments of the invention, the reinforcing structurecomprises one of the aforementioned ECM-mimicking biomaterialcompositions.

In some embodiments of the invention, the reinforcing structurecomprises one of the aforementioned ECM/ECM-mimicking biomaterialcompositions.

In some embodiments of the invention, the reinforcing structurecomprises a biocompatible metal, such as stainless steel and Nitinol®.

As stated above, in some embodiments of the invention, the tubularmembers of the invention and, hence, vascular grafts formed therefromand tubular member coatings further comprise at least one additionalbiologically active agent or composition, i.e. an agent that induces ormodulates a physiological or biological process, or cellular activity,e.g., induces proliferation, and/or growth and/or regeneration oftissue.

In a preferred embodiment, the biologically active agent is similarlyderived from an adolescent mammal, i.e. a mammal less than three (3)years of age.

Suitable biologically active agents include any of the aforementionedbiologically active agents, including, without limitation, theaforementioned cells and proteins.

In some embodiments of the invention, the biologically active agentspecifically comprises a growth factor selected from the groupcomprising transforming growth factor-alpha (TGF-α), transforming growthfactor-beta (TGF-β), fibroblast growth factor-2 (FGF-2), basicfibroblast growth factor (bFGF) and vascular epithelial growth factor(VEGF).

According to the invention, upon implanting a tubular member and, hence,a vascular graft formed therefrom proximate damaged biological tissue ofa subject, the growth factors link to and interact with at least onemolecule in the tubular member and/or a cell or molecule recruited bythe ECM and enhances cell and tissue proliferation, bioremodeling, andregeneration of new tissue structures.

By way of example, according to the invention, when a tubular memberand, hence, a vascular graft formed therefrom comprises a growth factoraugmented ECM composition and/or an ECM composition coating comprisingECM and an exogenously added growth factor, e.g. bFGF and/or VEGF, andthe tubular member is disposed proximate damaged biological tissue, thegrowth factor interacts with the endogenous heparin sulfate present inthe ECM and cells recruited by the ECM, wherein the tubular membermodulates inflammation and induces tissue proliferation,neovascularization, bioremodeling and regeneration of tissue.

In some embodiments of the invention, the biologically active agentcomprises a protein selected from the group comprising, withoutlimitation, collagen (types I-V), proteoglycans, glycosaminoglycans(GAGs), glycoproteins, heparins, chondroitin sulfate B (dermatansulfate), chondroitin sulfate A, heparin sulfates, hyaluronic acids,cytokines, cell-surface associated proteins, and cell adhesion molecules(CAMs).

In some embodiments of the invention, the cytokine is selected from thegroup comprising a stem cell factor (SCF), stromal cell-derived factor-1(SDF-1), granulocyte macrophage colony-stimulating factor (GM-CSF),interferon gamma (IFN-gamma), interleukin-3, interleukin-4,interleukin-8, interleukin-10, interleukin-13, leukemia inhibitoryfactor (LIF), amphiregulin, thrombospondin 1, thrombospondin 2,thrombospondin 3, thrombospondin 4, thrombospondin 5, and angiotensinconverting enzyme (ACE).

According to the invention, when a tubular member and, hence, a vasculargraft formed therefrom comprises a protein augmented ECM compositionand/or an ECM composition coating comprising ECM and an exogenouslyadded protein, e.g., cytokine, the protein similarly interacts with atleast one molecule in the tubular member and/or a cell or moleculerecruited by the ECM and similarly enhances cell and tissueproliferation, bioremodeling, and regeneration of new tissue structures.

In some embodiments, the tubular members of the invention and, hence,vascular grafts formed therefrom and tubular member coatings furthercomprise at least one pharmacological agent or composition (or drug),i.e. an agent or composition that is capable of producing a desiredbiological effect in vivo, e.g., stimulation or suppression ofapoptosis, stimulation or suppression of an immune response, etc.

Suitable pharmacological agents and compositions include any of theaforementioned agents, including, without limitation, antibiotics,anti-viral agents, analgesics, steroidal anti-inflammatories,non-steroidal anti-inflammatories, anti-neoplastics, anti-spasmodics,modulators of cell-extracellular matrix interactions, proteins,hormones, enzymes and enzyme inhibitors, anticoagulants and/orantithrombic agents, DNA, RNA, modified DNA and RNA, NSAIDs, inhibitorsof DNA, RNA or protein synthesis, polypeptides, oligonucleotides,polynucleotides, nucleoproteins, compounds modulating cell migration,compounds modulating proliferation and growth of tissue, andvasodilating agents.

In some embodiments of the invention, the pharmacological agentcomprises one of the aforementioned anti-inflammatory agents.

In some embodiments of the invention, the pharmacological agentcomprises a statin, i.e. a HMG-CoA reductase inhibitor. According to theinvention, suitable statins include, without limitation, atorvastatin(Lipitor®), cerivastatin, fluvastatin (Lescol®), lovastatin (Mevacor®,Altocor®, Altoprev®), mevastatin, pitavastatin (Livalo®, Pitava®),pravastatin (Pravachol®, Selektine®, Lipostat®), rosuvastatin(Crestor®), and simvastatin (Zocor®, Lipex®). Several actives comprisinga combination of a statin and another agent, such asezetimbe/simvastatin (Vytorin®), are also suitable.

Applicant has found that the noted statins exhibit numerous beneficialproperties that provide several beneficial biochemical actions oractivities; particularly, when delivered to damaged tissue with an ECMmaterial. Indeed, Applicant has found that when a statin is added to ECM(wherein a statin augmented ECM composition is formed) and the statinaugmented ECM composition is administered to damaged tissue, the statininteracts with the cells recruited by the ECM, wherein the statinaugmented ECM composition modulates inflammation of the damaged tissueby modulating several significant inflammatory processes, includingrestricting expression of monocytes chemoattractant protein 1 (MCP-1)and chemokine (C-C) motif ligand 2 (CCR2).

The properties and beneficial actions are further discussed inApplicant's Co-Pending application Ser. No. 13/328,287, filed on Dec.16, 2011, Ser. No. 13/373,569, filed on Sep. 24, 2012 and Ser. No.13/782,024, filed on Mar. 1, 2013; which are incorporated by referenceherein in their entirety.

Additional suitable pharmacological agents and compositions that can beemployed within the scope of the invention are disclosed in Pat. Pub.Nos. 20070014874, 20070014873, 20070014872, 20070014871, 20070014870,20070014869, and 20070014868; which are expressly incorporated byreference herein in its entirety.

According to the invention, the biologically active and pharmacologicalagents referenced above can comprise various forms.

In some embodiments of the invention, the biologically active andpharmacological agents, e.g. simvastatin, comprise microcapsules thatprovide delayed delivery of the agent contained therein.

In some embodiments, the tubular members of the invention and, hence,vascular grafts formed therefrom comprise a combination of ECM,polymeric, ECM-mimicking biomaterial composition, and/orECM/ECM-mimicking biomaterial composition coatings having variousbiologically active and/or pharmacological agents and/or properties,e.g. a an ECM composition coating comprising a growth factor and anECM-mimicking biomaterial composition coating comprising apharmacological agent, e.g. antiinflammatory.

In some embodiments, the tubular member coatings comprise modulateddegradation kinetics, wherein the gradual degradation of the coatingprovides a controlled release of biologically active and/orpharmacological agents incorporated therein.

In some embodiments, the tubular member coatings are configured toprovide a delivery gradient of various biologically active and/orpharmacological agent delivery profiles. By way of example, in someembodiments, biologically active and/or pharmacological agents aredisposed throughout various depths or thickness ranges of one or morecoatings.

In some embodiments, the tubular members of the invention and, hence,vascular grafts formed therefrom specifically comprise an ECMcomposition coating comprising anti-inflammatory growth factorsinterleukin-10 (IL-10) and transforming growth factor beta (TGF-β),which will suppress the inflammatory reaction leading to a chronicimmune response. According to the invention, during a chronic immuneresponse, IL-10 and TGF-β induce the expression of tissue inhibitor ofmetalloproteinase (TIMP), which inhibits matrix metalloproteinases(MMPs) that are responsible for ECM degradation during the inflammatoryresponse. Additionally, IL-10 and TGF-β promote the recruitment offibroblasts, which are the seminal cells responsible for ECM depositionand bioremodeling. As a result, IL-10, TGF-β, and the TIMPsconcomitantly promote ECM deposition and preservation, which thusaugments “modulated healing,” as defined herein.

In some embodiments, the tubular members of the invention and, hence,vascular grafts formed therefrom specifically comprise an ECMcomposition coating comprising at least one biologically active orpharmacological agent that provides a reinforcing anti-inflammatoryeffect either through direct reinforcement, i.e. targeting the sameinflammatory signaling pathway, or indirect reinforcement, i.e.targeting an alternate inflammatory signaling pathway. An example ofdirect reinforcement includes, without limitation, a combination ofIL-10, TGF-β and a glucocorticoid, all of which inhibit the expressionof seminal inflammatory cytokine interleukin-1 (IL-1). An example ofindirect reinforcement includes, without limitation, a combination ofIL-10, TGF-β and an NSAID, (Non-steroidal anti-inflammatory drug) whereIL-10 and TGF-β inhibit IL-1, and the NSAIDs inhibit the activity ofboth cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), and thereby,the synthesis of prostaglandins and thromboxanes.

According to the invention and indicated above, upon implanting atubular member of the invention and, hence, a vascular graft formedtherefrom to damaged or diseased biological tissue, “modulated healing”is effectuated. The tubular member also provides a vessel having asmooth, non-thrombogenic interior surface.

The term “modulated healing”, as used herein, and variants of thislanguage generally refer to the modulation (e.g., alteration, delay,retardation, reduction, etc.) of a process involving different cascadesor sequences of naturally occurring tissue repair in response tolocalized tissue damage or injury, substantially reducing theirinflammatory effect. Modulated healing, as used herein, includes manydifferent biologic processes, including epithelial growth, fibrindeposition, platelet activation and attachment, inhibition,proliferation and/or differentiation, connective fibrous tissueproduction and function, angiogenesis, and several stages of acuteand/or chronic inflammation, and their interplay with each other.

For example, in some embodiments, the tubular members of the inventionand, hence, vascular grafts formed therefrom are specifically formulated(or designed) to alter, delay, retard, reduce, and/or detain one or moreof the phases associated with healing of damaged tissue, including, butnot limited to, the inflammatory phase (e.g., platelet or fibrindeposition), and the proliferative phase when in contact with biologicaltissue.

In some embodiments, “modulated healing” refers to the ability of atubular member of the invention and, hence, a vascular graft formedtherefrom to restrict the expression of inflammatory components. By wayof example, as indicated above, when a tubular member comprises an ECMor ECM/ECM-mimicking biomaterial composition and/or an ECM orECM/ECM-mimicking biomaterial composition coating comprising a statinand the tubular member is disposed proximate damaged biological tissue,the tubular member restricts the expression of MCP-1 and CCR2.

In some embodiments, “modulated healing” means and includes the abilityof a tubular member of the invention and, hence, a vascular graft formedtherefrom to alter a substantial inflammatory phase (e.g., platelet orfibrin deposition) at the beginning of the tissue healing process. Asused herein, the phrases “alter a substantial inflammatory phase” refersto the ability of a tubular member to substantially reduce theinflammatory response at an injury site when in contact with biologicaltissue.

In such an instance, a minor amount of inflammation may ensue inresponse to tissue injury, but this level of inflammation response,e.g., platelet and/or fibrin deposition, is substantially reduced whencompared to inflammation that takes place in the absence of a tubularmember and, hence, graft of the invention.

The term, “modulated healing” also refers to the ability of a tubularmember of the invention and, hence, a vascular graft formed therefrom toinduce host tissue proliferation, bioremodeling, includingneovascularization, e.g., vasculogenesis, angiogenesis, andintussusception, and regeneration of tissue structures withsite-specific structural and functional properties.

Thus, in some embodiments, the term “modulated healing” also refers tothe ability of a tubular member and, hence, a vascular graft formedtherefrom to modulate inflammation and/or induce host tissueproliferation and remodeling. Again, by way of example, according to theinvention, when a tubular member comprises an ECM or ECM/ECM-mimickingbiomaterial composition and/or an ECM or ECM/ECM-mimicking biomaterialcomposition coating comprising a statin and the tubular member isdisposed proximate damaged biological tissue, the statin interacts withthe cells recruited by the ECM, wherein the tubular modulatesinflammation by, among other actions, restricting expression of MCP-1and CCR2 and induces tissue proliferation, bioremodeling andregeneration of tissue structures with site specific structural andfunctional properties.

By way of a further example, according to the invention, when a tubularmember and, hence, a vascular graft formed therefrom comprises a growthfactor augmented ECM composition and/or a coating comprising an ECMcomposition comprising ECM and an exogenously added growth factor, e.g.TGF-β, is disposed proximate damaged biological tissue, the growthfactor similarly interacts with the ECM and cells recruited by the ECM,wherein the tubular member modulates inflammation and induces tissueproliferation, bioremodeling and regeneration of tissue.

In some embodiments, the tubular members of the invention and, hence,vascular grafts formed therefrom and/or tubular member coatings providea single-stage agent delivery profile, i.e. comprise a single-stagedelivery vehicle, wherein a modulated dosage of an aforementionedbiologically active and/or pharmacological agent is provided.

According to the invention, the term “modulated dosage” as used herein,and variants of this language generally refer to the modulation (e.g.,alteration, delay, retardation, reduction, etc.) of a process involvingdifferent eluting or dispersal rates of an agent within biologicaltissue.

In some embodiments, the single-stage delivery vehicle comprisesencapsulated particulates of a biologically active and/orpharmacological agent.

In some embodiments, the encapsulation composition comprises one of theaforementioned ECM compositions.

In some embodiments, the encapsulation composition comprises abiodegradable polymeric composition comprising one of the aforementionedpolymeric materials.

In some embodiments, the encapsulation composition comprises one of theaforementioned ECM-mimicking biomaterial compositions.

In some embodiments, the encapsulation composition comprises one of theaforementioned ECM/ECM-mimicking biomaterial compositions.

In some embodiments, the encapsulation composition comprises an osmoticfluctuation inducing composition. According to the invention, suitableosmotic fluctuation inducing compositions include, without limitation,polyethylene glycol, alginate and dextran.

According to the invention, the term “osmotic fluctuation” as usedherein, and variants of this language generally refer to the modulationof the osmotic pressure gradient across a defined barrier.

For example, as is well known in the art, alginate is capable ofabsorbing 200-300 times its weight in water, which substantiallyincreases the osmotic pressure gradient of the alginate. The increasedosmotic pressure gradient of the alginate results in a rapid dispersalof an agent therefrom.

In some embodiments of the invention, the tubular members of theinvention and, hence, vascular grafts formed therefrom and/or tubularmember coatings provide a multi-stage agent delivery profile, i.e.comprise a multi-stage agent delivery vehicle, wherein a plurality ofthe aforementioned biologically active and/or pharmacological agents areadministered via a modulated dosage. By way of example, in someembodiments, the multi-stage delivery vehicle comprises encapsulatedparticulates comprising an antibiotic composition encapsulated in analginate composition having a statin incorporated therein, whichprovides a tiered modulated agent delivery.

In some embodiments, the multi-stage agent delivery vehicle comprises acombination of different biologically active and/or pharmacologicalagents. By way of example, in some embodiments, the multi-stage deliveryvehicle comprises encapsulated particulates comprising an encapsulatedgrowth factor concomitantly administered with an encapsulatedanti-inflammatory.

In some embodiments, the multi-stage delivery vehicle comprises aplurality of different biologically active and/or pharmacological agentsencapsulated in different encapsulation compositions. By way of example,in some embodiments, the multi-stage delivery vehicle comprisesencapsulated particulates comprising a growth factor encapsulated inalginate composition and a pharmacological agent encapsulated in a PGScomposition.

In some embodiments of the invention, the vascular grafts furthercomprise at least one anchoring mechanism, such as disclosed inCo-pending application Ser. Nos. 13/782,024 and 13/686,131; which areincorporated by reference herein in their entirety.

Referring now to FIGS. 1A and 1B, there is shown one embodiment of atubular member of the invention. As illustrated in FIG. 1A, the tubularmember 12 comprises a continuous member having proximal 14 and distal 16ends, and a lumen 18 that extends therethrough.

As indicated above, in a preferred embodiment of the invention, thetubular member 12 comprises a decellularized ECM material. As alsoindicated above, preferably, the ECM material is derived from anadolescent mammal, i.e. a mammal less than three (3) years of age.

According to the invention, the tubular member 12, and, hence vasculargrafts 10 a and 10 b (discussed below) formed therefrom, can havevarious diameters, e.g. 3.0 mm, 10.0 mm, etc.

In some embodiments of the invention, the tubular member 12 (or ECMmaterial thereof) further comprises at least one additional biologicallyactive agent or composition, i.e. an agent that induces or modulates aphysiological or biological process, or cellular activity, e.g., inducesproliferation, and/or growth and/or regeneration of tissue.

Suitable biologically active agents include any of the aforementionedbiologically active agents, including, without limitation, theaforementioned cells, growth factors and proteins.

In some embodiments, the tubular member 12 (or ECM material thereof)further comprises at least one pharmacological agent or composition (ordrug), i.e. an agent or composition that is capable of producing adesired biological effect in vivo, e.g., stimulation or suppression ofapoptosis, stimulation or suppression of an immune response, etc.

Suitable pharmacological agents and compositions include any of theaforementioned agents, including, without limitation, antibiotics,anti-viral agents, analgesics, and anti-inflammatories.

In some embodiments of the invention, the pharmacological agentcomprises a statin, i.e. a HMG-CoA reductase inhibitor.

Referring now to FIGS. 2A and 2B, there is shown one embodiment of avascular graft of the invention. As illustrated in FIG. 2A, the graft 10a comprises tubular member 12 having proximal 14 and distal 16 ends, anda lumen 18 that extends therethrough. The tubular member 12 furthercomprises at least one outer coating 20 disposed on the outer surface 11of the tubular member 12.

According to the invention, the coating 20 can comprise any of theaforementioned coatings and/or a combination thereof.

Referring now to FIGS. 3A and 3B, there is shown another embodiment of avascular graft of the invention. As illustrated in FIG. 3A, the graft 10b similarly comprises tubular member 12 having at least one innercoating outer coating 20 disposed on the outer surface 11 of the tubularmember 12. In this embodiment, the tubular member 12 further comprisesat least one inner coating 22 disposed on the inner surface 13 (or lumensurface) of the tubular member 12.

According to the invention, the inner coating 22 can similarly compriseany of the aforementioned coatings and/or a combination thereof.

As will readily be appreciated by one having ordinary skill in the art,the present invention provides numerous advantages compared to prior artprosthetic valves. Among the advantages are the following:

-   -   The provision of vascular grafts that substantially reduce or        eliminate (i) the risk of thrombosis, (ii) intimal hyperplasia        after intervention in a vessel, (iii) the harsh biological        responses associated with conventional polymeric and metal        prostheses, and (iv) the formation of biofilm, inflammation and        infection.    -   The provision of vascular grafts, which can be effectively        employed to treat, reconstruct, replace and improve biological        functions or promote the growth of new cardiovascular tissue in        a cardiovascular structure.    -   The provision of vascular grafts that induce host tissue        proliferation, bioremodeling and regeneration of new tissue and        tissue structures with site-specific structural and functional        properties.    -   The provision of vascular grafts, which are capable of        administering a pharmacological agent to host tissue and,        thereby produce a desired biological and/or therapeutic effect.

Without departing from the spirit and scope of this invention, one ofordinary skill can make various changes and modifications to theinvention to adapt it to various usages and conditions. As such, thesechanges and modifications are properly, equitably, and intended to be,within the full range of equivalence of the following claims.

What is claimed is:
 1. A vascular graft for treating damaged or diseased tissue in cardiovascular vessels, comprising: a tubular member comprising first acellular extracellular matrix (ECM) material and an ECM-mimicking biomaterial comprising poly(glycerol sebacate) (PGS), said tubular member comprising an outer surface and a lumen that extends therethrough, said lumen defining a tubular member inner surface. said tubular member further comprising at least one biodegradable coating disposed on said tubular member outer surface.
 2. The vascular graft of claim 1, wherein said first acellular ECM material is selected from the group consisting of small intestine submucosa (SIS), urinary bladder submucosa (UBS), urinary basement membrane (UBM), liver basement membrane (LBM), stomach submucosa (SS), mesothelial tissue, subcutaneous extracellular matrix, large intestine extracellular matrix, placental extracellular matrix, omamentum extracellular matrix, heart extracellular matrix and lung extracellular matrix.
 3. The vascular graft of claim 2, wherein said first acellular ECM material comprises adolescent ECM material.
 4. The vascular graft of claim 2, wherein said tubular member further comprises at least one exogenously added first biologically active agent.
 5. The vascular graft of claim 4, wherein said first biologically active agent comprises a cell selected from the group consisting of a human embryonic stem cell, fetal cardiomyocyte, myofibroblast, and mesenchymal stem cell.
 6. The vascular graft of claim 4, wherein said first biologically active agent comprises a growth factor selected from the group consisting of a transforming growth factor-alpha (TGF-α), transforming growth factor-beta (TGF-β), fibroblast growth factor-2 (FGF-2), basic fibroblast growth factor (bFGF), and vascular epithelial growth factor (VEGF).
 7. The vascular graft of claim 1, wherein said tubular member further comprises at least a first pharmacological agent.
 8. The vascular graft of claim 7, wherein said first pharmacological agent comprises an agent selected from the group consisting of an antibiotic, anti-viral agent, analgesic, anti-inflammatory, anti-neoplastic, anti-spasmodic, and anticoagulant and antithrombic agent.
 9. The vascular graft of claim 7, wherein said first pharmacological agent comprises a statin selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin.
 10. The vascular graft of claim 1, wherein said biodegradable coating comprises a first ECM composition coating comprising a second ECM material selected from the group consisting of SIS, UBS, UBM, LBM, SS, mesothelial tissue, subcutaneous extracellular matrix, large intestine extracellular matrix, placental extracellular matrix, ornomentum extracellular matrix, heart extracellular matrix and lung extracellular matrix.
 11. The vascular graft of claim 1, wherein said biodegradable coating comprises a first polymeric composition coating comprising a first biodegradable polymeric material selected from the group consisting of poly(ε-caprolactone-co-glycolide)(PCL), polyhydroxy-alkonate (PHA), polylactide (PLLA) and polyglycolide (PLGA) and its copolymers, and polyanhydride.
 12. The vascular graft of claim 1, wherein said biodegradable coating comprises a first ECM-mimicking biomaterial composition comprising PGS.
 13. The vascular graft of claim 1, wherein said biodegradable coating comprises an first ECM/ECM-mimicking biomaterial composition comprising a third ECM material and PGS.
 14. The vascular graft of claim 13, wherein said third ECM material is selected from the group consisting of SIS, UBS, UBM, LBM, SS, mesothelial tissue, subcutaneous extracellular matrix, large intestine extracellular matrix, placental extracellular matrix, omomentum extracellular matrix, heart extracellular matrix and lung extracellular matrix.
 15. The vascular graft of claim 13, wherein said first ECM/ECM-mimicking biomaterial composition further comprises a second biodegradable polymeric material selected from the group consisting of PCL, PHA, PLLA and PLGA and its copolymers, and polyanhydride.
 16. The vascular graft of claim 1, wherein said biodegradable coating further comprises at least a second biologically active agent.
 17. The vascular graft of claim 16, wherein said second biologically active agent comprises a cell selected from the group consisting of a human embryonic stem cell, fetal cardiomyocyte, myofibroblast, and mesenchymal stem cell.
 18. The vascular graft of claim 16, wherein said second biologically active agent comprises a growth factor selected from the group consisting of TGF-α, TGF-β, FGF-2, bFGF, and VEGF.
 19. The vascular graft of claim 1, wherein said biodegradable coating further comprises at least a second pharmacological agent.
 20. The vascular graft of claim 19, wherein said second pharmacological agent comprises an agent selected from the group consisting of an antibiotic, anti-viral agent, analgesic, anti-inflammatory, anti-neoplastic, anti-spasmodic, and anticoagulant and antithrombic agent.
 21. The vascular graft of claim 19, wherein said second pharmacological agent comprises a statin selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin.
 22. The vascular graft of claim 1, wherein said tubular member further comprises a first reinforcing structure, said first reinforcing structure being disposed proximate said tubular member outer surface.
 23. The vascular graft of claim 22, wherein said first reinforcing structure comprises a woven structure.
 24. The vascular graft of claim 22, wherein said first reinforcing structure comprises a second polymeric composition coating comprising a third biodegradable polymeric material selected from the group consisting of PCL, PHA, PLLA and PLGA and its copolymers, and polyanhydride.
 25. The vascular graft of claim 22, wherein said first reinforcing structure comprises a second ECM-mimicking biomaterial composition comprising PGS.
 26. The vascular graft of claim 22, wherein said first reinforcing structure comprises a second ECM/ECM-mimicking biomaterial composition comprising a fourth ECM material selected from the group consisting of SIS, UBS, UBM, LBM, SS, mesothelial tissue, subcutaneous extracellular matrix, large intestine extracellular matrix, placental extracellular matrix, ornomentum extracellular matrix, heart extracellular matrix and lung extracellular matrix, and PGS.
 27. The vascular graft of claim 22, wherein said second ECM/ECM-mimicking biomaterial composition further comprises a fourth biodegradable polymeric material selected from the group consisting of PCL, PHA, PLLA and PLGA and its copolymers, and polyanhydride.
 28. The vascular graft of claim 22, wherein said tubular member further comprises a second reinforcing structure.
 29. The vascular graft of claim 28, wherein said second reinforcing structure comprises a mesh structure.
 30. The vascular graft of claim 29, wherein said mesh reinforcing structure comprises Nitinol®. 